This invention generally pertains to the field of psychiatry. In particular, this invention pertains to the discovery that agents which inhibit the binding of cortisol to its receptor can be used in methods of ameliorating psychosis, including the psychotic component of pathologies or conditions with psychotic symptoms.
This invention is directed to a method for treating psychosis whose pathogenesis is related to glucocorticoid regulatory dysfunction. The types of psychosis treated by the methods of the invention must be distinguished from the older definition of psychosis, which referred to schizophrenia and manic states. Schizophrenia and manic states are not associated with dysfunction of the glucocorticoid regulatory pathway and there is no basis to believe that possibility. Thus, the treatment methods of the invention encompass the modem usage of the term psychosis, i.e., non-schizophrenia and non-manic state associated psychosis.
There has been historic confusion in the definition of psychosis. This is, in part, based on a lack of understanding of a common pathophysiologic mechanism causing psychosis in various conditions. For example, Oberlander, et al., WO 98/26785, teaches use of an anti-glucocorticoid to treat schizophrenia and manic states. However, schizophrenia and manic states are are believed to be the result of abnormal nerve structure, i.e., xe2x80x9chard-wiringxe2x80x9d problems. In contrast, it is believed that the pathophysiology of psychosis (the term used in its modem sense, as used in the instant invention) is related to neurochemical (glucocorticoid regulatory) problems. This theory is extended by the instant invention, in which it was surprisingly discovered that agents which inhibit the binding of cortisol to its receptor can be used to treat psychosis.
Today it is known that psychotic patients can be distinguished from other psychiatric problems in that they have a glucocorticoid regulatory dysfunction. In contrast, patients with schizophrenia and manic states do not have glucocorticoid regulatory dysfunction (see, e.g., Rothschild (1982) Br. J. Psychiatry 141:471-474; Clower (1986) J. Clin. Psychopharmacol. 6:363-365). Thus, schizophrenia and manic states are not within the scope of the definition of xe2x80x9cpsychosisxe2x80x9d (as defined either by the medical profession, or, as used herein), and thus are not treated by the methods of the invention.
In most species, including man, the physiological glucocorticoid is cortisol (hydrocortisone). Glucocorticoids are secreted in response to ACTH (corticotropin), which shows both circadian rhythm variation and elevations in response to stress and food. Cortisol levels are responsive within minutes to many physical and psychological stresses, including trauma, surgery, exercise, anxiety and depression. Cortisol is a steroid and acts by binding to an intracellular, glucocorticoid receptor (GR). In man, glucocorticoid receptors are present in two forms: a ligand-binding GR-alpha of 777 amino acids; and, a GR-beta isoform which differs in only the last fifteen amino acids. The two types of GR have high affinity for their specific ligands, and are considered to function through the same transduction pathways.
The biologic effects of cortisol, including those caused by hypercortisolemia, can be modulated at the GR level using receptor antagonists. Several different classes of agents are able to block the physiologic effects of GR-agonist binding. These antagonists include compositions which, by binding to GR, block the ability of an agonist to effectively bind to and/or activate the GR. One such known GR antagonist, mifepristone, has been found to be an effective anti-glucocorticoid agent in humans (Bertagna (1984) J. Clin. Endocrinol. Metab. 59:25). Mifepristone binds to the GR with high affinity, with a K of dissociation xe2x89xa610xe2x88x929 M (Cadepond (1997) Annu. Rev. Med. 48:129).
Patients with some forms of psychiatric illnesses have been found to have increased levels of cortisol (Krishnan (1992) Prog. Neuro-Psychopharrnacol. and Biol. Psychiat. 16:913-920). For example, some patients with depressed mood have had their mood improve with treatments which lower the levels of cortisol. In some individuals, reversing increased cortisol levels using inhibitors of steroid biosynthesis can be effective in treating depression (Murphy (1991) J. Steroid Biochem. Mol. Biol. 39:239; Murphy (1991) J. Clin. Psychopharmcol. 11:121; Dhar (1989) Clin. Invest. Med. 12:B27). Alternatively, some depressed individuals can be responsive to treatments which block the effect of cortisol, as by administering GR antagonists (Van Look (1995) Human Reproduction Update 1:19-34). In one study, a patient with depression secondary to Cushing""s Syndrome (hyperadrenocorticism) was responsive to a high dose, up to 1400 mg per day, of GR antagonist mifepristone (Nieman (1985) J. Clin Endocrinol. Metab. 61:536). Another study which used mifepristone to treat Cushing""s syndrome found that it improved the patients"" conditions, including their psychiatric status (Chrousos, pp 273-284, In: Baulieu, ed. The Antiprogestin Steroid RU 486 and Human Fertility Control. Plenum Press, New York (1989), Sartor (1996) Clin. Obstetrics and Gynecol. 39:506-510). Mifepristone has been used to treat major depression. Using from about 2.5 to 4.4 mg/kg per day for periods up to eight weeks, one group found that four patients with chronic severe depression, who were resistant to conventional therapies, responded to treatment (Murphy (1993) J. Psychiatr. Neurosci. 18:209).
Psychosis has also been associated with Cushing""s syndrome (Gerson (1985) Can. J. Psychiatry 30:223-224; Saad (1984) Am. J. Med. 76:759-766). Mifepristone has been used to treat acute psychiatric disturbances secondary to Cushing""s syndrome. One study showed that a relatively high dose of mifepristone (400 to 800 mg per day) was useful in rapidly reversing acute psychosis in patients with severe Cushing Syndrome due to adrenal cancers and ectopic secretion of ACTH from lung cancer (Van der Lely (1991) Ann. Intern. Med. 114:143; Van der Lely (1993) Pharmacy World and Science 15:89-90; Sartor (1996) supra).
Psychotic major depression has long been recognized as a distinct psychiatric illness, having both psychotic and depressive components. In a differential diagnosis, it is important that psychotic major depression be distinguished from nonpsychotic major depression, because effective treatments and patterns of response to pharmacologic therapies for psychotic major depression are very different from those relating to non-psychotic major depression. Successful treatment depends on the accuracy of the initial diagnosis. (Glassman (1981) Arch. Gen. Psychiatry 38:424-427, Schatzberg (1992) Am. J. Psychiatr. 149:733-745, Schatzberg (1988) Annals N.Y. Acad. of Sci.537:462). Psychotic major depression is very common. It has been estimated that twenty five percent of depressed patients admitted to the hospital have psychotic major depression (Coryell (1984) J. Nerv. Ment. Dis. 172:521).
Before this invention, there was to fast-acting effective treatment without significant side effects for the treatment of psychosis or the psychotic component of illnesses and conditions associated with psychosis, such as psychotic major depression. Individuals suffering from psychotic major depression have a low placebo response rate and respond poorly to antidepressant therapy alone, i.e., without concurrent treatment with antipsychotic medication (Glassman (1975) Am. J. Psychiatry 132:716-719; Avery (1979) Am. J. Psychiatry 135:559-562). While psychotic depression can respond to electroconvulsive therapy (ECT), this form of treatment is controversial, can have significant side effects, has a relatively slow response rate and has a high level of related morbidity. Similarly, another commonly used treatment for psychotic major depression, a combination therapy of currently available antipsychotic and antidepressant medications, has a slow onset of action and a relatively high rate of morbidity (Minter (1979) J. Nerv. Ment. Dis. 167:726-733).
Thus, there exists a great need for a more effective and safer treatment for psychosis and illnesses and conditions associated with psychosis, including psychotic major depression. There is a great need for a new treatment for psychotic major depression which has a quick response time, has few side effects, decreases the amount of time a patient must be institutionalized and has a lower rate of morbidity. Furthermore, there exists a variety of conditions which have a psychotic element for which there is no known cure or effective treatment. These include schizoaffective disorder, Alzheimer""s Disease and cocaine addiction. Thus, there exists a great need for a safe and effective treatment for these conditions. The present invention fulfills these and other needs.
The invention is directed to a method of treating psychosis associated with glucocorticoid related dysfunction by administration of an amount of a glucocorticoid receptor antagonist effective to ameliorate the psychosis, with the proviso that the patient not be suffering from Cushing""s Syndrome. In alternative embodiments of this method, the psychosis is associated with psychotic major depression, schizoaffective disorder, Alzheimer""s Disease and cocaine addiction.
In further embodiments, the glucocorticoid receptor antagonist used in the methods can comprise a steroidal skeleton with at least one phenyl-containing moiety in the 11-beta position of the steroidal skeleton. The phenyl-containing moiety in the 11-beta position of the steroidal skeleton can be a dimethylaminophenyl moiety.
In alternative embodiments of the invention, the glucocorticoid receptor antagonist can comprise mifepristone (RU486), RU009 or RU044. The glucocorticoid receptor antagonist can be administered in a daily amount of between about 8 to 20 mg per kilogram of body weight per day, or, in a daily amount of about 8 to 12 mg per kilogram of body weight per day. The glucocorticoid receptor antagonist can be administered for about four days. It can be administered in a daily amount of about 600 mg per day. The administration can be once per day. Its mode of administration can be oral or transdermal.
In a preferred embodiment, the invention relates to a method of ameliorating psychotic depression comprising administering a mifepristone in a daily amount of about 8 to 12 mg per kilogram of body weight per day, wherein the administration continues for a period of about four days.
The invention also relates to a kit for the amelioration of psychosis in a human, the kit comprising: a glucocorticoid receptor antagonist; and, an instructional material teaching the indications, dosage and schedule of administration of the glucocorticoid receptor antagonist. The kit""s instructional material can indicate that the glucocorticoid receptor antagonist can be administered in a daily amount of about 8 to 12 mg per kilogram of body weight per day. The instructional material can indicate that the administration of the glucocorticoid receptor antagonist can continue for a period of about four days.
In one embodiment, the kit is for the amelioration of psychosis as a component of psychotic major depression and the instructional material indicates that the glucocorticoid receptor antagonist can be used for the treatment of psychotic major depression. In a preferred embodiment, the kit""s glucocorticoid receptor antagonist is mifepristone, which can be in tablet form.